Cancer is characterized that cell cluster called as tumor caused by abnormal and uncontrolled cell growth, is formed, permeated into neighboring tissue and severe to be transferred to other organ, which is called as neoplasia. Over than 20 million peoples per year are suffered with cancer in the world and among them 6 million people per year were died from the disease. The origin of cancer is classified into internal factor e.g., genetic factor, immunological factor etc and external factor e.g., various chemical substances, radioactive ray, virus etc. Cancer may occur when the balance between oncogene and tumor suppressor genes is collapsed by above explained factors.
Histone is a nuclear protein bound to nucleus DNA and reversible acetylation reaction of histones occurs at s-amino group of positively charged lysine tail with reversibility. Since the reaction relates to the formation of highly structure of chromatin, it is reported to be correlated with the regulation of the cell cycle and gene expression accompanied with non-histone proteins.
The balance of acetylated status is sustained with the regulation of two enzyme complexes, histone acetyltransferase (HAT) and histone deacetylase (HDAC), and the change of acetylation level is reported to be essential in the change of gene expression. Therefore, the acetylated state of histone can be regulated by compounds inhibiting HDAC activity, according to the structure, for example, (1) butyrate having short chain fatty acid structure (Newmark et al., Cancer Lett. 78, pp 1-5, 1994), (2) trichostatin A, suberoylanilide hydroxamic acid (SAHA) and oxamflatin having hydroxamic acid structure (Tsuji et al., J. Antibiot. (Tokyo) 29, pp 1-6, 1976; Richon et al., Proc. Natl. Acad. Sci. USA, 95, pp 3003-3007, 1998; Kim et al., Oncogene 18, pp 2461-2470, 1999), (3) cyclic tetrapeptide structure including the 2-amino-8-oxo-9,10-epoxy-decanoyl (AOE); trapoxin A (Kijima et al., J. Biol. Chem. 268, 22429-22435, 1993), (4) cyclic tetrapeptide structure including the AOE; FR901228 and apicidin (Nakjima et al., Exp. Cell Res. 241, pp 126-33, 1998; Darkin-Rattray et al., Proc. Natl. Acad. Sci. USA, 93, pp 13143-13147, 1996), (5) benzamide structure; MS-27-275 (Saito et al., Proc. Natl. Acad. Sci. USA, 96, pp 4592-4597, 1999).
It has been known that these compounds inhibit HDAC enzyme, induce hyper-acetylation of histone protein, cause to hyper-expression of a specific protein family such as tumor inhibiting factor and inhibit the growth of cancer cell resulting in cancer cell death. Accordingly, the compound inhibiting HDAC selectively can be developed to be a promising candidate drug inhibiting cancer cell and inducing to cell death.
However, there has been not reported or disclosed about novel oxopiperidine compound showing potent inhibiting activity of HDAC activity and anticancer activity in any of above cited literatures, the disclosures of which are incorporated herein by reference.
To investigate novel compound having oxopiperidine skeleton showing potent inhibiting activity of HDAC activity and anticancer activity, the inventors of present invention have intensively carried out in vitro experiment concerning the inhibition effect on the HDAC enzyme. As a result of the investigation, the inventors finally completed the present invention by confirming that the novel compound of the present invention inhibited HDAC enzyme and it can be useful as an anti-cancer agent.